How do Ras isoforms attain oncogenic specificity and efficiency at the membrane? Oncogenic KRas (KRas4A and KRas4B), HRas, and NRas differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. We consider determinants that may bias isoform-specific effectors activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity. We focus on the mechanism of PI3Kα activation at the atomic level, the structural basis for KRas4B activation of PI3Kα, how Ras promotes Raf activation and signaling at the membrane and finally pharmacological implications.

Ras signaling: PI3K and Raf activation at the membrane

2019 Fall National Meeting

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